NOVEL SYNERGISTIC THERAPY FOR CYSTIC FIBROSIS

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Individuals with a clinical diagnosis of cystic fibrosis (CF) and increased sweat sodium and chloride concentration suffer from chronic and progressive pulmonary infection. Bacteria from several genera have been isolated from the lower respiratory tract of CF patients, but P. aeruginosa are the most prevalent. Antibiotic therapy directed against this bacterium improves pulmonary function. However, repeated courses of antibiotic therapy are associated with emergence of resistant strains and drug toxicity. Aerosolization of high doses of tobramycin into the lower respiratory tract of CF patients produces bactericidal concentrations in sputum and improves pulmonary function. Drug toxicity is not detectable and the frequency of emergence of resistant bacteria is not increased. High doses of tobramycin are required because sputum antagonizes tobramycin bioactivity through DNA binding of the antibiotic and through its high content of divalent cations. We have found that pretreatment of sputum with recombinant human DNase (rhDNase) mitigates much of the antagonism of tobramycin activity. Since aerosol administration of rhDNase improves pulmonary function by decreasing sputum viscosity (and by inference, increasing muco-ciliary clearance), we hypothesize that "aerosol administration of rhDNase and tobramycin to CF patients improves pulmonary function than either agent alone". To test this hypothesis we will: 1) determine the minimal bactericidal concentration of tobramycin in DNase treated sputum for 30 P. aeruginosa isolates 2) devise an aerosol delivery system permitting coadministration of tobramycin and rhDNase, 3) conduct a pilot study to verify adequacy of the delivery system, the sputum pharmacokinetics of both agents and their effect on pulmonary ventilation, and 4) conduct a multicenter, double-masked, randomized, placebo-controlled parallel study of each agent alone and in combination on FEV1 and sputum bacterial density. This therapy has the opportunity to prolong the life of CF patients until correction of the basic defect is feasible.